High salt diet is often associated with increased vascular resistance and arterial pressure in salt-sensitive individuals. In normal individuals, however, high salt diet does not increase the arterial pressure significantly, suggesting possible vascular protective mechanisms. Endothelin-1 (ET-1) activates ETA and ETa receptors. Although the role of ETA receptors in vascular contraction and hypertension has been studied extensively, the importance of ETa receptors in modulating the vascular function and arterial pressure particularly during high salt diet is less clear. Preliminary data suggest that ET-1 production is enhanced during high sodium intake. Data also suggest that chronic blockade of ETa receptors results in a salt-sensitive form of hypertension; however, the vascular and cellular mechanisms involved are unclear. The overall objective of this proposal is to test the hypothesis that normally during high salt diet an increase in ET-1 production and enhancement of its ETA-mediated vascular contraction pathways are counterbalanced by enhanced ETa-mediated vascular relaxation pathways, thus preventing excessive increases in vascular resistance and arterial pressure. Accordingly, chronic blockade of Eta receptors during high salt diet will not only decrease vascular relaxation, but also enhance vascular reactivity leading to increased vascular resistance and salt-sensitive hypertension. The decreased vascular relaxation occurs as a result of inhibition of the endothelium-dependent nitric oxide-cGMP, prostacyclincAMP and/or hyperpolarizing factor pathway. The increased vascular reactivity occurs as a result of increased [Ca2+]i and protein kinase C activity in vascular smooth muscle. The increases in vascular reactivity, [Ca2+]i and PKC activity during chronic blockade of ETa receptors and high salt diet occur as a result of unbalanced stimulation of ETA receptors. To test this hypothesis chronically-instrumented rats on normal and high sodium diets and nontreated or treated with ETa and ETA receptor antagonists will be used. Integrated analysis will be used to investigate the relation between ETa-mediated vascular relaxation and ETA-mediated vascular contraction in isolated renal vessels, and the arterial pressure in vivo. These studies should help understand better the vascular protective mechanisms during high salt diet in normal individuals and the pathophysiological basis of the increased vascular resistance in salt-sensitive hypertension.